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Prognostic impact of HNF4α expression in TTF-1-negative non-squamous NSCLC treated with immune checkpoint inhibitor
Hirokazu Iso1, Ryo Ariyasu2, Syunsuke Fujishima2
1Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
Introduction:
Thyroid transcription factor-1 (TTF-1)-negative status is associated with poor response to immune checkpoint inhibitor (ICI); however, the underlying reasons remain unclear. Hepatocyte nuclear factor 4 alpha (HNF4α) is a nuclear receptor mutually exclusive with TTF-1 and is associated with cancer cell proliferation and metastasis. This study evaluated the impact of HNF4α expression on survival outcomes in patients with TTF-1-negative non-squamous non-small cell lung cancer (non-Sq NSCLC) treated with ICI.
Methods:
We conducted this single-center retrospective study that analyzed patients with advanced or recurrent non-Sq NSCLC who received ICI therapy. Based on immunohistochemical analysis, the patients were classified into three groups: (1) TTF-1 negative and HNF4α positive, (2) TTF-1 negative and HNF4α negative, and (3) TTF-1 positive. Kaplan-Meier analysis was used to estimate overall survival (OS), and the log-rank test was used to compare intergroup differences.
Results:
388 patients treated with ICI were included: 54 TTF-1 negative HNF4α positive, 48 TTF-1 negative HNF4α negative, and 286 TTF-1 positive. The median OS was significantly worse in the TTF-1-negative HNF4α-positive group than in the TTF-1-positive group (12.0 vs. 32.3 months; Hazard ratio (HR): 2.14 [95 % confidence interval (CI): 1.54-2.99], p < 0.001). Meanwhile, the median OS of the TTF-1-negative HNF4α-positive group was equivalent to that of the TTF-1-positive group (32.2 vs. 32.3 months; HR: 1.03 [95 % CI: 0.68-1.54], p = 0.90). Multivariate analysis identified HNF4α as an independent poor prognostic factor. Subgroup analyses restricted to patients with adenocarcinoma and those receiving first-line chemo-immunotherapy demonstrated similar trends.
Conclusion:
HNF4α expression in TTF-1-negative non-Sq NSCLC was associated with worse prognosis in patients treated with ICI.
Insights
Hepatocyte nuclear factor 4 alpha (HNF4α) expression in thyroid transcription factor-1 (TTF-1)-negative non-squamous non-small cell lung cancer (NSCLC) is linked to poorer outcomes with immune checkpoint inhibitors (ICIs). This finding highlights HNF4α as a potential prognostic marker in TTF-1-negative NSCLC patients receiving ICI therapy.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Pathology
Background:
- Thyroid transcription factor-1 (TTF-1)-negative status in non-squamous non-small cell lung cancer (non-Sq NSCLC) correlates with diminished response to immune checkpoint inhibitors (ICIs).
- Hepatocyte nuclear factor 4 alpha (HNF4α), a nuclear receptor mutually exclusive with TTF-1, is implicated in cancer proliferation and metastasis.
- The prognostic significance of HNF4α in TTF-1-negative NSCLC patients undergoing ICI therapy remains largely unexplored.
Purpose of the Study:
- To investigate the impact of HNF4α expression on survival outcomes in patients with TTF-1-negative non-Sq NSCLC treated with ICIs.
- To determine if HNF4α expression serves as an independent prognostic factor in this patient cohort.
Main Methods:
- A single-center retrospective study analyzed 388 patients with advanced or recurrent non-Sq NSCLC receiving ICI therapy.
- Patients were stratified by immunohistochemical analysis into three groups: TTF-1 negative/HNF4α positive, TTF-1 negative/HNF4α negative, and TTF-1 positive.
- Overall survival (OS) was estimated using Kaplan-Meier analysis, with log-rank tests comparing intergroup differences.
Main Results:
- The TTF-1-negative/HNF4α-positive group exhibited significantly worse median OS (12.0 months) compared to the TTF-1-positive group (32.3 months; HR: 2.14).
- The median OS for the TTF-1-negative/HNF4α-positive group was comparable to the TTF-1-positive group (32.2 vs. 32.3 months; HR: 1.03).
- Multivariate analysis identified HNF4α as an independent poor prognostic factor in TTF-1-negative NSCLC patients treated with ICIs.
Conclusions:
- HNF4α expression in TTF-1-negative non-Sq NSCLC is associated with a worse prognosis for patients receiving ICI therapy.
- HNF4α may serve as a valuable biomarker for predicting treatment response and guiding therapeutic strategies in this specific NSCLC subtype.
